Ferroptotic neutrophils eradicate chemotherapy-induced immunity in breast cancer (Neutrophils)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1177346 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Inducing ferroptosis in tumor cells serves as a promising strategy for treating malignancies that are refractory to traditional treatment modalities. However, the consequences of ferroptosis in immune cells in the tumor microenvironment (TME) are not completely understood. In this study, we found that neutrophils in chemoresistant breast cancer exhibited notable vulnerability to ferroptosis. In chemoresistant neutrophils, the cellular phospholipid profile was reprogrammed owing to a deficiency in membrane-bound O-acyltransferase domain-containing 1 (MBOAT1), shifting the preference of the phospholipid fatty acid pattern from monounsaturated fatty acids (MUFAs) to polyunsaturated fatty acids (PUFAs), thereby increasing susceptibility to ferroptosis. Ferroptotic neutrophils significantly suppress the proliferation and cytotoxicity of antitumor CD8 T cells via PGE2, IDO, and oxidized lipids. Furthermore, we found that neutrophil ferroptosis was closely associated with a distinctive subset of IL-1+ CXCL3+ CD4 (Fer-CD4) T lymphocytes that were enriched in chemoresistant tumors. Fer-CD4 T cells regulated neutrophil ferroptosis through MBOAT1 modulation via IL-1/IL-1R1/NF-B signaling. Moreover, we revealed that there is crosstalk between neutrophils and Fer-CD4 T cells, during which Fer-CD4 T cells replenish the neutrophil pool of the TME via CXCL3, IL-8, and S100A9. The ferroptotic neutrophils in turn promote Fer-CD4 T cell differentiation, resulting in extensive neutrophil ferroptosis. In spontaneously tumorigenic mice, targeting IL-1+ CD4 T cells or IL-1R1+ neutrophils disrupted this crosstalk, suppressed neutrophil ferroptosis, enhanced antitumor immunity, and overcame chemoresistance. Our findings revealed the immune-reshaping capacity of neutrophil ferroptosis and its reciprocal feedback regulation with Fer-CD4 T cells, identifying promising targets for restoring anticancer immunosurveillance and reversing chemoresistance
2025-09-01 | GSE280204 | GEO
Project description:LC3-associated phagocytosis of neutrophils trigger tumor ferroptotic cell death in glioblastoma
| PRJNA1099203 | ENA
Project description:Necrosis is commonly found in various solid tumors and predicts worse outcome. Chronic ischemia can initiate tumor necrosis, but how the damaged tissue further expands is unclear. Previous studies found that neutrophils associate with necrosis and could contribute to necrosis development in glioblastoma (GBM) by transferring myeloperoxidase (MPO)-containing granules into tumor cells and inducing tumor cell ferroptosis. How the neutrophilic granule transfer occurs is unknown. Here, through an unbiased small molecule screen, we found that statins can inhibit neutrophil-induced tumor cell death by blocking the neutrophilic content transfer into tumor cells. Surprisingly, we found that neutrophils are engulfed by tumor cells before they are fragmented and release the MPO-containing contents in tumor cells. This process involves LC3-associated phagocytosis (LAP) and can be blocked by inhibiting the Vps34-UVRAG-containing PI3K complex. Inhibition of MPO or depletion of Vps34 in an orthotopic xenograft GBM mouse model reduced necrosis formation and allowed tumor-bearing mice to survive longer. Therefore, this study revealed that the neutrophilic granule transfer involves LAP-mediated neutrophil internalization, which then triggers tumor ferroptotic cell death in glioblastoma. Blocking this process may improve prognosis of GBM.
2024-04-29 | GSE263766 | GEO
Project description:In this study, we found that myeloid PTEN can determine chemotherapy responsiveness by promoting NLRP3-dependent antitumor immunity and suggest that it might be a potential biomarker to predict the chemotherapy responses and manipulating NLRP3/IL-1might be able to overcome the chemotherapy resistance in PTEN-loss patients.
2020-04-16 | PXD018597 |
Project description:To investigate effects of standard-of-care neoadjuvant carboplatin and paclitaxel chemotherapy on T cell immunity, we surveyed changes in the peripheral T cell receptor repertoire. We performed bulk TCR sequencing of peripheral blood before chemotherapy (baseline), after 3 cycles (C3) and after 6 cycles (C6).
2022-06-22 | GSE206339 | GEO
Project description:Although acute lymphoblastic leukemia (ALL) is highly responsive to chemotherapy, it is unknown how and which host immune factors influence the long-term remission of this cancer. To this end, we systematically evaluated the effects of T cell immunity on ALL chemotherapy outcomes. Using murine BCR-ABL1 ALL model, we showed that loss of total T cells, CD4 cells, or CD8 cells in the host drastically increased leukemia relapse following dasatinib or cytotoxic chemotherapy. Although ABL1 mutations emerged early during dasatinib treatment in both immunocompetent and immunocompromised hosts, T cell immunity was essential for suppressing the outgrowth of drug-resistant leukemia. Bulk and single-cell transcriptome profiling of T cells during therapy pointed to the activation Type I immunity-related cytokine signaling linked to long-term leukemia remission in mice. Consistent with these observations, IFNG and IL12 directly modulated dasatinib anti-leukemia efficacy in vivo. Finally, we evaluated peripheral blood immune cell composition in 102 children with ALL during chemotherapy and observed a significant association of T cell abundance with treatment outcomes. Together, these results suggest that T cell immunity plays pivotal roles in maintaining long-term remission of ALL, highlighting that the interplay between host immunity and drug resistance can be harnessed to improve ALL chemotherapy outcomes.
2022-08-03 | GSE201765 | GEO
Project description:Induction of trained immunity by beta-glucan has been shown to promote transcriptomic alterations in myeloid cells. Neutrophils are involved in the immune response against tumors and can promote or inhibit tumor growth. In this study, we performed RNA sequencing in TAN from mice in order to investigate the impact of trained immunity on the transcriptomic profile of neutrophils in the tumor setting.
2020-10-30 | GSE139450 | GEO
Project description:Neutrophils have emerged as diverse regulators of tissue states, displaying functions in both the resolution and promotion of tissue inflammation. While neutrophils have widely been associated with tumor promotion, immune suppression, and poor patient outcome, we provide evidence to support direct tumor cytotoxic properties of neutrophils. Using various models of murine breast cancer; we establish that TLR-mediated engagement, combined with complex I inhibition, within the breast tumor microenvironment, acting either directly or indirectly on neutrophils, primes these innate immune cells to acquire direct tumor killing properties, both in vitro and in vivo, and independently of CD8+ T cell immunity. TLR engagement stimulates emergency granulopoiesis, increasing levels of neutrophils in the circulation and infiltrating into tumors without inducing the formation of a pro-metastatic niche. Mechanistically, we show that systemic administration of various TLR agonists, while increasing systemic inflammation, elevates NFB signalling in neutrophils, to contribute to their tumoricidal functions. Moreover, using bulk- and single-cell RNA sequencing, along with proteomics approaches, we show that neutrophils which are trained to acquire these anti-tumorigenic functions both enhance secretory granule production and increase expression NADPH-oxidase machinery. Concomitantly, these tumoricidal neutrophils increase production of toxic levels of reactive oxygen species, which can be overcome with myeloperoxidase inhibitors or overexpression of ROS scavengers. Taken together, we describe a new class of neutrophils that possess direct and intrinsic tumoricidal functions, which can be exploited to eradicate immune cold breast tumors which otherwise are refractory to standard immunotherapies, including immune checkpoint blockade.
2025-06-04 | PXD054085 | Pride
Project description:Classical dendritic cells (cDC) are professional antigen presenting cells (APC) that regulate immunity and tolerance. Neutrophil-derived cells with properties of DCs (nAPC) are observed after culture of neutrophils with cytokines and in human diseases. Here, we show that FcgR-mediated endocytosis of antigen-antibody complexes or an anti-FcgRIIIB-antigen conjugate converts neutrophils into nAPCs that, in contrast to those generated with cytokines alone, activate T cells to levels observed with cDCs and elicit CD8 T cell-dependent anti-tumor immunity. Single cell transcript analyses and validation studies implicate the transcription factor PU.1 in neutrophil to nAPC conversion. In humans, nAPC frequency in lupus patient blood containing IgG-immune complexes correlates with disease. Moreover, conjugate treatment of neutrophils from individuals with myeloid neoplasms that harbor neoantigens or those who are vaccinated against bacterial toxins generates nAPCs that activate autologous T cells. Thus, anti-FcgRIIIB-antigen conjugate-induced conversion of neutrophils to immunogenic nAPCs may represent a new immunotherapy for cancer and infectious diseases.
2021-04-30 | GSE173569 | GEO
Project description:Improved T cell immunity following neoadjuvant chemotherapy in ovarian cancer
| PRJNA850267 | ENA